The intein-mediated cyclization of peptides is known from DE 699 30 164 T2.
Anti-Aß directed antibodies for treating Alzheimer's disease are known from DeMattos et al. (DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J.-C., Paul, S. M., Holtzman, D. M. (2001). Peripheral anti-Aß antibody alters CNS and plasma Aß clearance and decreases brain Aß burden in a mouse model of Alzheimer's disease. In: PNAS, Vol. 98, pgs. 8850-8855).
However, there is still no drug available for the treatment of Alzheimer's disease (AD, Latin Morbus Alzheimer) which acts to combat the cause. Drugs that are used are able to alleviate some symptoms at best, but cannot slow, let alone stop, the progression of the disease.
A number of substances exist that, in animal experiments, are able to achieve some successes in terms of prevention, but not necessarily in the treatment, of Alzheimer's disease.
One trait of Alzheimer's disease is extracellular deposits of the amyloid beta peptide (A beta peptide, Aß, or Aß peptide). These deposits of the A beta peptide in plaque are typically found in the brains of AD patients post mortem. This is the reason why various forms of the A beta peptide, such as fibrils, are considered to be responsible for the development and progression of the diseases. Additionally, for some years now, small, freely diffusable A beta oligomers have been regarded as the primary causative factor in the development and progression of AD. A beta monomers are continuously created in our body and are presumably not toxic per se. There is speculation as to whether A beta monomers agglomerate to form A beta oligomers randomly as a function of the concentration thereof, which ultimately results from formation and decomposition rates in the body, and thus, with increasing age, are increasingly likely to do so spontaneously. Once A beta oligomers have developed, it is possible that they multiply by way of a prion-like mechanism and ultimately lead to disease.
At present, several substances exist that reduce the concentration of A beta monomers in a wide variety of ways, for example by way of gamma secretase inhibition or modulation, A beta-binding antibodies, and so forth, which appears to suffice to provide successful preventive action in animal experiments (animals are usually already undergoing treatment before the symptoms of the disease fully manifest themselves). In clinical human studies, in phases II and III, only individuals that have been clearly diagnosed with Alzheimer's disease are allowed to be treated. This is where all these substances have failed so far. It is possible that, after the onset of the disease, a small or moderate decrease in the A beta monomer concentration is no longer sufficient to prevent the development of increasingly greater amounts of A beta oligomers.
To date, there it is not possible to diagnose Alzheimer's disease before symptoms appear. Today, Alzheimers disease is primarily detected through neuropsychological tests on persons already suffering from symptoms of dementia. Furthermore, other diseases, such as traumas, can be excluded by way of various examination methods. However, it is known that A beta oligomers, and subsequently plaque, develop in the brain of patients up to 20 years prior to the appearance of symptoms and cause irreversible damage. Molecular probes, which are intravenously injected into the patient and bind to A beta oligomers and plaque after passing the blood-brain barrier, can be rendered visible by way of imaging methods, and thus allow an early diagnosis of Alzheimer's disease.
The disadvantage of the existing A beta-binding substances is that they have insufficient affinity to prevent the multiplication of A beta oligomers.
Another disadvantage is that there are no probes for in vivo imaging methods which bind specifically to A beta species and render these visible. Since A beta oligomers play such an important and early role in the history of the disease, exactly this would be desirable.